This invention is directed to the preparation and use of the R-isomer of cefuroxime axetil in a form substantially free of the S-isomer.
Cefuroxime is a cephalosporin antibiotic having a broad spectrum of activity against both gram-positive and gram-negative microorganisms. The compound's use is limited to injectable administration because it is poorly absorbed from the gastro-intestinal tract following oral dosing. Crisp et al., in GB2,145,409A, describes the synthesis of the 1-acetoxyethyl ester of cefuroxime, now referred to as cefuroxime axetil. Cefuroxime axetil is a prodrug of cefuroxime which can be orally administered, thereby permitting more convenient and wider therapeutic use of cefuroxime. Unfortunately, cefuroxime axetil suffers from several deficiencies, including being rapidly hydrolyzed in the intestine, leaving substantial unabsorbable cefuroxime. Campbell et al., in Biochemical Pharmacology, Vol. 36, No. 14, pp 2317-2324, 1987, report the isolation and partial characterization of an esterase enzyme which is said to be responsible for converting cefuroxime axetil to cefuroxime in the gut. The ester portion of cefuroxime axetil, namely the 1-acetoxyethyl group, contains an asymmetric carbon atom at the 1-position, and accordingly cefuroxime axetil exists in the form of a mixture of the R- and S-isomers. Oral administration of the R,S-mixture of cefuroxime axetil results in only about fifty percent bioavailability of the cefuroxime antibiotic, due to low overall solutility and the rapid hydrolysis of the ester group by esterase enzymes located in the gut. The unabsorbable cefuroxime remaining in the gut lumen is suspected to be the cause of incomplete bioavailability, and the gastro-intestinal irritation generally observed.
We have now discovered that the individual S-isomer of cefuroxime axetil is hydrolyzed in animals much more rapidly than the R-isomer. Accordingly, an object of this invention is to provide R-cefuroxime axetil substantially free of the S-isomer, and to provide a method for administering R-cefuroxime axetil and not administering the S-isomer. Such selective administration results in surprisingly greater bioavailability of cefuroxime, and thus dramatically reduces the amount of unabsorbable cefuroxime remaining in the gut lumen, thereby diminishing adverse side effects attributable to cefuroxime.